The present invention relates to a novel process for preparing compounds of the formula (I) ##STR2## where R.sub.1 and R.sub.2 are individually selected from the group consisting of methyl and hydrogen or R.sub.1 and R.sub.2 in combination form an ethylene bridge. More particularly, the present invention relates to a novel process for forming the compounds (S)(+)-1,2-bis(3,5-dioxopiperazinyl)propane and (R)(-)-1,2-bis(3,5-dioxopiper-azinyl)propane.
(S)(+)-1,2-bis(3,5-dioxopiperazinyl)propane is described in U.S. Pat. Nos. 3,941,790 and 4,275,063 to Creighton. It is known to display activity against tumors and other forms of cancer and to be useful as a synergist in combination with other anticancer agents. In particular, the compound has been found to exhibit activity with respect to sarcoma, lymphosarcoma and leukeima and to be particularly effective when used in a regimen in combination with Adriamycin.
Various methods for preparing compounds of the formula (I) are known in the art. The Creighton patents disclose two methods. In one (S)-1,2-diaminopropane is reacted with chloroacetic acid to form (S)-1,2-diaminopropane tetraacetic acid. The tetraacid is reacted with formamide under nitrogen at elevated temperature to yield the compound of formula (I). The second method consists of preparing the aforementioned tetraacetic acid as above, transforming it to the tetraamide by reaction with ammonia, and cyclizing the product
British Pat. No. 978,724 describes another method for forming the tetraacetic acid in which diamines are reacted tetranitrile which is saponified. Bersworth et al. in U.S. Pat. No. 2,461,519 teaches a method for producing 1,2-diaminopropane tetracarboxylic acid by reacting 1,2-diaminopropane with formaldehyde and sodium cyanide at an alkaline pH.
These methods have not been satisfactory. In the first method of Creighton, the reaction of the diamine with chloroacetic acid requires a long period of time and separation of the tetraacid is difficult. Yields are relatively low. The second method of Creighton is also limited in terms of yield. Lin, Y.T. et al. Radiopharm. 1976 12(4) 592 attempted to form the tetraacid of 1,2-propane diamine using formaldehyde and sodium cyanide without success.